Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UMLS:C0699790 (
colon cancer
)
28,837
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cross-resistance to drugs remains an unsolved problem in cancer chemotherapy. This study elucidates a molecular mechanism of cross-resistance to diverse inhibitors of
nicotinamide phosphoribosyltransferase
(
NAMPT
) with anticancer activity. We generated a variant of the human
colon cancer
cell line HCT116, HCT116R
FK866
, which exhibited primary resistance to the potent
NAMPT
inhibitor FK866, and was approximately 1,000-fold less sensitive to the drug than the parental HCT116. HCT116R
FK866
was found to be cross-resistant to diverse
NAMPT
inhibitors, including CHS-828, GNE-617, and STF-118804. Whole-exon sequencing revealed two point mutations (H191R and K342R) in
NAMPT
in HCT116R
FK866
, only one of which (K342R) was present in the parental HCT116. Importantly, the protein level,
NAMPT
enzyme activity, and intracellular NAD
+
level were similar between HCT116R
FK866
and HCT116. Hence, we investigated
NAMPT
-binding partners in both cell lines by focused proteomic analyses. The amount of
NAMPT
precipitated with anti-
NAMPT
monoclonal antibody was much higher in HCT116R
FK866
than in the parental. Furthermore, in HCT116, but not in HCT116R
FK866
,
NAMPT
was revealed to interact with POTE ankyrin domain family member E and beta-actin. Thus, these results suggest that
NAMPT
usually interacts with the two partner proteins, and the H191R mutation may prevent the interactions, resulting in resistance to diverse
NAMPT
inhibitors.
...
PMID:Cross resistance to diverse anticancer nicotinamide phosphoribosyltransferase inhibitors induced by FK866 treatment. 2966 58
Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD
+
) and a reduced form (NADH). NAD
+
plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD
+
and NADH) could be used as biomarker for
colon cancer
progression. Here, we showed that the NAD(H) pool size and NAD
+
/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD
+
salvage pathway mediated by
nicotinamide phosphoribosyltransferase
(
NAMPT
). The
NAMPT
expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two-photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of
NAMPT
, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that
NAMPT
-mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression.
...
PMID:Increased nicotinamide adenine dinucleotide pool promotes colon cancer progression by suppressing reactive oxygen species level. 3045 89
